DE2707915A1 - ORGANIC COMPOUNDS, THEIR PRODUCTION AND USE - Google Patents

Description

SANDOZ-PATENT-GMBH Case 100-454 4

Loerrach

Organic compounds, their manufacture and use

The invention relates to prostaglandins, in particular ergolin-8-yl-alkyl esters, thioesters and amides of Prostanoic acids.

The invention relates in particular to compounds of the formula I,

D '^ Y Z-COWR XR ₁

wherein, in the prostanoic acid moiety, D is a group of the formula

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Dl

D2

OR ₁

OH

D3

D4

D7

D5

or

D8

D6

stands, in which A is a radical of the formula a)

α β

a)

S t

wherein 1 to 3 of the methine groups denoted by α, β, Γ or S have been replaced by nitrogen or a radical of the formula b)

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b)

means, wherein either one of the ring members L and N represents nitrogen and the other represent methine, or L and M each represent nitrogen, 1 to 3 of with α, β, γ, or <£ "methine groups indicated can be replaced by nitrogen, and the six-membered ring can be unsubstituted or monosubstituted by alkylamino, dialkylamino, alkoxy, alkylthio or halogen , the alkyl groups independently of one another having 1-5 carbon atoms,

X for -CH ₂ -CH ₂ - or -CH = CH- (trans), Y for -CH ₂ -CH ₂ - or -CH = CH- (cis or trans),

^ 2
Z stands for -CH ₂ -CH ₂ - or -CH - ^> CH- (cis or trans), R _{1 is} an alkyl group with 1-10 carbon atoms or a cycloalkyl group with 3-9 carbon atoms, R _{2 is} hydrogen or an alkyl group with 1 -7 carbon atoms, R ₃ and R ₄ independently of one another are hydrogen, an alkanoyl group with 1-20 carbon atoms or the benzoyl group, w oxygen, sulfur or the -NH group, and the alkylergoline part R represents the remainder of the formula II

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II

where η is 1 or 2, R _{5 is} hydrogen, an alkyl group with 1-4 carbon atoms or the benzyl group, R _g and R .. are independently hydrogen or halogen, R_ is an alkyl group with 1-4 carbon atoms, however not tert. Butyl means

1) Rg and R ₉ each for hydrogen, or

2) Rg and R- together form a bond, or

3) Rg is hydrogen and R _g represent an alkoxy group having 1-4 carbon atoms.

In formula I, the 15-OR group is in the α or β configuration and the 8-ergoline side chain is in the α or β configuration.

It should be noted that the term prostanoic acid used here is natural or includes synthetic prostaglandins. The term ergoline used here includes natural or synthetic ergoline derivatives.

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Al

If A stands for a radical of the formula a), this means, for example, pyrazolyl, imidazolyl, triazolyl, e.g. 1,2,4-triazol-1-yl, or tetrazolyl, e.g. 1,2,3,4-tetrazol-1-yl.

If A stands for a radical of the formula b), then - * preferably 0 to 2 methine groups of the six-membered ring are replaced by nitrogen. Preferably M is represents nitrogen and the remainder of the formula b) preferably represents benzimidazolyl or purinyl. The rest of formula b) is preferably unsubstituted and, if this is monosubstituted, the ring substituents are preferably in the α or S positions . The alkyl group of the ring substituents preferably has 1-2 carbon atoms and in particular represents the methyl group.

The preferred ring substituent is the dialkylamino group.

If R. stands for an alkyl group, this has preferably 5-8 carbon atoms. The α-position can be branched. Suitable examples are the 1-pentyl, 1-heptyl, 2-methyl-2-hexyl, 2-hexyl or the 2-octyl group.

If R 1 denotes a cycloalkyl group, then this stands for example for cyclopentyl or cyclohexyl.

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AU

If R stands for an alkanoyl group, it has conveniently 2-5 carbon atoms and means e.g. the acetyl group.

If R. stands for an alkanoyl group, this conveniently has 8-20 carbon atoms and is e.g. for the n-octanoyl or lauroyl group.

If R _{5 is} an alkyl group, this conveniently stands for methyl.

The alkyl group of the substituent R_ conveniently has 1-3 carbon atoms and is, for example, methyl or isopropyl.

If Rg denotes an alkoxy group, then this stands conveniently for methoxy.

A suitable halogen is chlorine or bromine, in particular bromine.

The following individual meanings in the prostanoic acid part are preferred:

D preferably for D4 or D6> A preferably for imidazolyl; X preferably for -CH = CH- (trans);

Υ preferably for -CH = CH- (cis) or -CH ₂ -CH ₂ -?

Z preferably for -CH ₂ -CH ₂ - or -CH ---XH- (trans) \

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R- preferably for alkyl J

R-, R- and R. preferably for hydrogenJ

the -OR ₃ -GrUpPe is preferably in the α-configuration _} W, preferably for oxygen or in particular -NH-.

The following individual meanings in the alkylergoline part R are preferred:

η preferably for 1}

R _{5 represents} hydrogen or methyl;

R. ^ for Me thy Ij

(i) R ₈ , R ₉ , R ₆ and R ₁₀ each represent hydrogen »

(ii) R ₈ and R ₉ together form a bond, R ₆ and R ₁₀ each represent hydrogen »

(iii) R ₈ , R ₉ and R ₁₀ each represent hydrogen, R _{g represents} bromine;

(iv) R _ß and R ₉ each for hydrogen, R _ß and R ₁₀ each for bromine}

(v) Rg and R ₉ together form a bond, R ₆ for bromine and R .. for hydrogen.

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away

The vorliet, ^ln invention relates to a process for preparing the above-mentioned esters, thioesters and amides by reacting a corresponding prostanoic acid or its reactive acid derivative with a corresponding 8-Hydroxyalkylergolin, 8-Thioalkylergolin or 3 Aminoalkylercolin.

The invention particularly relates to a method

a) for the preparation of compounds of the formula I by adding compounds of the formula III,

D 'Y Z-COOH ___

\ III

"X" ¹

where D, R., R_, R_, X, Y and Z have the above meaning, or its reactive acid derivatives with compounds of the formula IV,

H-WR IV

wherein R and W have the above meaning, converts, or

b) for the preparation of compounds of the formula Ia,

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/ Π

Yes

in which R, R., R-, R ₃ / W ₁ X, Y and Z have the above meaning by starting from compounds of the formula Ib,

Z-CCWR

Ib

in which A, R, R ₁ , R ₂ , R ₃ , W, X, Y and Z have the above meanings, the radical A splits off.

Process a) can be used for the preparation of esters, thioesters and amides of prostanoic acid Manner can be carried out taking into account the other substituents. It is conveniently a reactive acid derivative of prostanoic acid formed in situ using carbonyldiimidazole. To activate Hydroxyalkylergoline and thioalkylerfoline in particular are expediently catalytic Quantities of a solution of imidazole sodium in tetrahydrofuran were added. When using a connection of the Formula III, in which D stands for D2, an addition of the imidazole formed takes place with the formation of a compound of the formula I, in which D is D6 and A is imidazol-1-yl stand. For the preparation of compounds of the formula I in which D stands for D2 and for the alternative preparation

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At

of amides can therefore preferably be other reactive Acid derivatives, e.g. 2-thiopyridyl derivatives, are used,

Process b) is preferably carried out in the presence of an alkanol, e.g. methanol. Suitable temperatures are, for example, between about 0 ° and 50 ° C, for example room temperature. The reaction times are generally up to 30 hours. The process can be carried out in the presence of an inert organic solvent, for example Tetrahydrofuran or methylene chloride will. The process can also be carried out in water as a solvent. At pH values greater than 7.0 e.g. to 9.0 the response time can be shortened. To accelerate the cleavage, sodium or Potassium bicarbonate, sodium acetate or a tert. Amine, such as pyridine or triethylamine, can be used.

Process b) is the more advantageous process for the preparation of compounds of the formula Ia, in particular when W is oxygen or sulfur.

The invention also relates to the compounds of the used as starting compounds for process a) Formula IHa,

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-COOH

HIa

where A, R-, R, R_, X, Y and Z have the above meaning, to which one can get by

c) compounds of the formula IHb,

IHb

in which R., R-, R-, X, Y and Z have the above meanings, with amines introducing the radical A.

Process c) can be carried out in a manner known per se. The reaction is expediently carried out at temperatures from 0 to 40 ^° C., preferably at room temperature, in an inert organic solvent.

In certain cases, e.g. in the reaction with purine, an isomerization of the amine takes place, so that one 2 end products of the formula IHa are obtained (see e.g. Example 4)

The invention also relates to the compounds of the formula III in which D is D8, to which one can, for example

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can get by

d) for the preparation of compounds of the formula III, in which D is D8, and one of the substituents R_ and R _{A is} hydrogen and the other of these substituents is an alkanoyl group with 1-20 carbon atoms or benasyl, from compounds of the formula V,

OR ₁

Z-COOH

wherein A, R-, R-, X, Y and Z are as defined above, and one of the substituents R ₁₁ and R _{12 is} an alkanoyl group having 1-20 carbon atoms or benzoyl and the other is a protecting group which splits off the protecting group, or

e) for the preparation of compounds of the formula III in which D is D8 and at least one of the substituents R ₃ and R _{4 is} an alkanoyl group or benzoyl, compounds of the formula III in which D is D8 and at least one of the substituents R, and R. hydrogen

3 4

means acylated, or £) for the preparation of compounds of the formula never

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Z-COOH

HlC

in which A, R., R ₂ / R_, X, Y and Z have the above meanings, the carbonyl group in position 9 is selectively reduced in compounds of the formula IHa.

The process d) can be carried out in a suitable for the cleavage of protective groups, for example the tetrahydro-2H-pyran-2-yl group, can be carried out in the manner customary in prostaglandin chemistry. The ones suitable for the procedure Reaction conditions are described in Example 6e).

The acylation of process e) can be carried out in a manner known for the acylation of such compounds Consideration of the other substituents can be carried out. In example 6d) are suitable reaction conditions described.

~ The reduction of method f) can be done using suitable reducing agents which do not act on the other substituents are carried out. For example sodium borohydride can be used.

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Suitable reaction conditions are described in Example 6c). The α- and β-isomers obtained can be separated in a manner known per se.

It should be noted that the processes mentioned are preferably carried out using pure starting compounds and reagents, for example anhydrous. The methods are preferably carried out in a nitrogen atmosphere.

The prostaglandins are cleaned in a manner known per se.

The compounds appearing in the form of free bases of the formula I and compounds of Formula III wherein D represents D6 or D8 can be converted into their acid addition salts and vice versa. Tartaric acid and methanesulfonic acid should be mentioned among the acids suitable for salt formation.

The prostaglandins can be racemic or in one of the both optically active forms are present. The optically active forms can be used in a manner known per se, e.g. from optically active starting compounds.

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If the production of the starting products is not described, these are by processes known per se or analogously to those described here (e.g. in the examples) or analogously to processes known per se manufacturable.

The ergolin-8-yl-alkyl esters, thioesters and amides of Prostanoic acids show more beneficial pharmacological prostaglandin-like effects than their counterparts Prostanoic acids. In particular, they bring about a decrease in arterial blood pressure.

The ergolin-8-yl-alkyl esters, thioesters and amides, in particular, where D stands for D6 or D8, moreover, have the effect of inhibiting platelet aggregation.

The compounds of the formula III in which D stands for D6 or D8 also cause a lowering of the arterial Blood pressure and an inhibition of platelet aggregation in those for the esters, thioesters and amides specified doses.

The ergolin-8-yl-alkyl esters, thioesters and amides as well as the compounds of the formula III, in which D stands for D6 or D8, can be administered in the form of their pharmaceutically acceptable acid addition salts, the salts having the same potency as the corresponding ones free bases. The salts can be prepared in a manner known per se.

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The invention also relates to pharmaceutical preparations, the ergolen-8-yl alkyl esters, thioesters or -amides as defined above, or compounds of the formula III in which D is D6 or D8, in free form or in the form their pharmaceutically acceptable acid addition salts and pharmaceutically acceptable diluents or carriers, contain. The preparations can be administered, for example, in the form of a solution.

The following examples illustrate the invention explain, all temperatures are given in degrees Celsius and are uncorrected.

IR refers to the IR spectrum of one in methylene chloride dissolved sample, unless otherwise stated.

The NMR data are consistent with the proposed structures match.

The vacuum commonly used is 10 mm Hg and the high vacuum 0.1 mm Hg. The term used here Lysergyl stands for 6-methyl-9,10-didehydro-8ß-hydroxymethyl-ergoline.

Unless otherwise indicated, the compounds prepared below are optically active and the absolute ones Configurations on the C-8 or C-12 correspond to those of the Prostanoic acid.

The term used in the following "eis- or trans - (+) - or (-) - methylene "refers to the respective (+) or (-) optically active forms of the cis- or trans-2- (2'-bromine-

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ethyl) cycloprop-l-yl-carboxylic acid used for production the corresponding optically active compound of

Formula III, in which Z is -CH-CH-, in per se known manner can be used.

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Example 1; 11α, 15S-dihydroxy-9-keto-13-trans ~ pröstenic acid-dihydroisolysergylamide [method a)]

A solution of 150 mg of pure prostaglandin E. in 4 ml of absolute dimethylformamide is made with 76 mg of carbonyldiimidazole added and stirred under nitrogen at room temperature for 3 1/2 hours. Thereupon 130 mg of finely powdered Dihydroisolysergylamine, added. After stirring for 7 days at room temperature, the solvent becomes at room temperature evaporated under high vacuum and the oily residue on 250 g of Sephadex LH 20 with methylene chloride Addition of 1% methanol chronographed, whereby one arrives at the title compound.

IR: 1740, 1660, 1520 cm " ¹

The free base is converted into the methanesulfonate by reaction with methanesulfonic acid.

Preparation of esters of formula I;

Analogously to Example 1 and using corresponding prostaglandins of the formula III and compounds of the formula IV, wherein W is oxygen, which together with a Freshly prepared catalytic amount of imidazole sodium in tetrahydrofuran is added to the following esters of the formula I:

a) Sa ^ l ^ lSS-Trihydroxy-Scis ^ lStrahs-proetadienoic acid lysergylester, Melting point of the hydrogen tartrate 117-120 ° C,

b) lla, 15S-dihydroxy-9-keto-13'ans-prostenic acid lysergyl-

ester, m.p. of hydrogen tartrate 158-160 ° C, 709846/0675

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c) 11α, lSS-dihydro - ^ - keto-lStrans-prostenic acid- (2 ', 13 ^L dibromo) dihydrolysergyl ester,

IR: 1740 cm "" ¹ (wide)

d) 11α, lSS-dihydroxy-iJ-keto-SciSflStrans-prostadienic acid lysgyl ester,

IR: 1740 cm "" ¹ (wide)

e) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid- (l'-methyl) lysergyl ester,

IR: 1740, 1735 (shoulder) cm " ¹

f) Ha, 15S-dihydroxy-9-keto-13-trans-prostenic acid (10'amethoxy) dihydrolysis ergyl ester IR: 1740 cm " ¹ (wide)

g) lla, 15S-dihydroxy-9-keto-13-trans-prostenoic acid-2- (2 · -

chloro-6'-methylergoline-8 ¹ ß-yl) ethyl ester, IR: 1740, 1735 cm " ¹

h) 11a, 15S-dihydroxy-9-keto-15-methyl-2,3-trans - (-) - methylene-13-trans-prostenic acid lysergylester, IR: 1740, 1730 cm " ¹

i)

Prostadic acid lysgyl ester, IR: 1745, 1735 (shoulder) cm " ¹

j) lla ^ SS-Dihydroxy ^ -keto-prostanoic acid lysgyl ester, IR: 1740 (broad) cm " ¹

k) lla ^ SR-dihydroxy ^ -keto-ieR-methyl-scis-prosteneic acid lysergylester,

IR: 1740, 1735 (shoulder) cm " ¹

1) lla, 15R-dihydroxy-9-keto-16R-methyl-2,3-trans - (+) -

methylene-5cis-prostenic acid lysgyl ester,

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m) 15-cyclohexyl-lla, 15R-dihydroxy-9-keto-16,17,18,19, 20-pentane scis-prostenic acid lysgyl ester,
IR: 1740 (wide) cm " ¹

η) ll <x, 15R-dihydroxy-9-keto-16R-methyl ~ 2,3-trans - (-) - methylene-scis-prostanoic acid lysgyl ester,
IR: 1740, 1735 (shoulder) cm " ¹

Analogously to Example 1 and using prostaglandins of the formula III, in which D is D2, or the corresponding prostaglandins of the formula III, in which D is D6, and corresponding compounds of the formula IV, in which W is oxygen, together with a catalytic one
Amount of Imidazole Sodium in Tetrahydrofuran.

aa) 15S-hydroxy-lla-imidazol-l'-yl ~ 9-keto-5cis, 13-transprostadienoic acid lysgyl ester,

IR: 3450, 1740, 1730 cm " ¹

ab) lSR-Hydroxy-lla-imidazol-l'-yl ^ -keto-Scis ^ Stransprostadiensäurelysergylester,

IR: 3550, 3450, 1745-1740 cm " ¹

ac) lSS-Hydroxy-lla-imidazol-l'-yl - ^ - keto-lStrans-prosten-

acid lysgyl ester, melting point of the hydrogen tartrate 104-106 ° C,

ad) lSS-hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13transprostadienäuredihydroisolysergylester,

IR: 3450. 1740, 1720, 1500 cm " ¹

ae) 15S-hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13trans-

Prostadienoic acid (2x, 13'-dibromo) dihydrolysis ergyl ester, IRj 3450, 1740, 1715, 1500 cm " ¹

af) 15S-hydroxy-9-keto-lla-l ', 2 ¹ , 4'-triazol-l'-yl-scis,

13 trans-prostatic acid lysgyl ester, cm 709846/0675

IR: 1740, 1720 cm " ¹

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ag) lSR-Hydroxy-lla-imidazol-l'-yl ^ -keto-ieR-methyl-scisprostenic acid lysgyl ester, IR: 1740, 1720, 1500 cm " ¹

ah) 15S-hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13-transsprostadienoic acid- (l'-methyl) -lysergylester,

IRs 1740, 1725 cm " ¹

ai) 15-Cyclohexyl-15R-hydroxy-lla-imidazol-l ^l -yl-9-keto-16, 17,18,19,20-pentanor-5cis, 13trans-prostadienoic acid lysergy1-

ester,
IR: 1740, 1720 cm " ¹

aj) 15R-Hydroxy-lla-imidazol-l'-yl-9-keto-16R-methyl-2,3-trans - (- J-methylen-scis-prostenic acid lysergylester, IR: 1740, 1720 cm " ¹ ,

ak) 15S-Hydroxy-lla-imidazol-l ^l -yl-9-keto-13-trans-prostenoic acid- (2 ¹ , 13'-dibrono) -dihydrolysergylester, IR: 1740, 1715, 1500 cm " ¹ ,

al) 15R-Hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13transprostadienäuredihydroisolysergylester, IR: 3450, 1740, 1720, 1500 cm " ¹ .

Preparation of thioesters of formula I:

Analogous to Example 1, but using suitable prostaglandins and suitable thiols from Fornel IV together the following compounds are obtained with catalytic amounts of sodium imidazole in tetrahydrofuran of formula I:

ba) lla, 15S-dihydroxy-9-keto-13.trans-prostenic acid lysergylthioester,
IR: 1740, 1695 cm " ¹

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bb) 15S-hydroxy-imidazol-l'-yl-9-keto-5cis _/ 13trans-prosta-

dienoic acid lysergylthioester (based on prostaglandin A ₉ ), IR: 1740, 1700 cm " ¹

Preparation of amides of the formula I;

Analogous to Example 1, but using suitable prostaglandins and suitable amines of the formula IV the following compounds of the formula Ii are obtained

ca) 11a, 15S-dihydroxy-9-keto-13-trans-prostenic acid lysgylamide,

IR: (CH ₂ Cl ₂ + CH ₃ OH): 3400 (broad), 1740, 1660, 1520 cm " ¹

cb) 11a, lSS-dihydroxy-SJ-keto-lStrans-prostenic acid dihydrolysergylamide, ₍

IR: 1740, 1665, 1520 cm " ¹

cc) Ha7l5S-dihydroxy-9-keto-13-trans-prostenoic acid-2- (6 · - methylergoline-8'ß-y ^ -ethylamide, IR: 3400, 1740, 1660, 1520 cm " ¹

cd) 11a, 15R-dihydroxy-9-keto-16R-methyl-2,3-trans- (-) - methylene-scis-prostenic acid lysgylamide,

IR: 1740, 1665, 1520 cm " ¹

ce) 9a, lla, 15S-trihydroxy-5cis, 13trans-prostadienoic acid lysis 1 ami d, IR: 1660, 1520 cm " ¹

c ^f ) 11a, 15S-dihydroxy-9-keto-prostanoic acid lysgylamide,

IR: (CH ₂ Cl ₂ + CH ₃ OH): 3400 (broad), 1740, 1660, 1520 cm " ¹

cg) 15S-Hydroxy-9-keto-5cis, 13trans-prostadienoic acid lysergylamide, IR: 1740, 1660, 1520 cm " ¹

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ch) ISS-Hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13-transsprostadienoic acid- (I ¹ -methyl) -ysergylamide, IR: 1725, 1660, 1520 cm " ¹

EI) ISS-hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13transprostadiensäure-2- (6'-methyl-ergoline-8 ß ^l-yl) -äthylamid, IR: 1725, 1665, 1525 cm " ¹

cj) lSS-acetoxy-lloc-imidazol-l'-yl-S-keto-Scis ^ Stransprostadiensäurelysergylamid,
IR: 1730 (wide), 1660, 1520 cm " ¹

ck) 15S-Hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13-transprostadienoic acid lysgylamide,
IR: 3450, 1740, 1665, 1520 cm " ¹

el) lSS-hydroxy-lla-imidazol-l'-yl-g-keto-lS-transprostan-

acid lysergylamide,
IR: 1725, 1665, 1525 cm " ¹ ,

where for the examples ch) to el) a suitable prostaglandin of the formula I, in which D is D2, is used.

Using the method described in Example 1, the following esters, thioesters and amides of the formula I are obtained, in which the part R has the meanings Lysergy], Dihydrolysergyl, Isolysergyl, Dihydroisolysergyl, 2-Bromlysergyl, 13-Bromdihydrolysergyl, 2,13-Dibromdihydrolysergyl, 10a -MethoxydihydroIysergy1, lOa-Methoxydihydroisolysergy1, 2,13-dibromo-lOa-methoxydihydrolysergyl, 2- or 13-bromo-10amethoxydihydrolysergyl and the prostanoic acid part has the meanings

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16,16-dimethyl
16,16-dimethyl
15-methyl
15-methyl ₃₀

16R- and S-methyl-13,14-dihydro PGE ₃

11-deoxy-PGE, its 15epi-isomer and its 5,6-dihydro- and 5,6,13,14-tetrahydro derivative

PGE, / its 15epi isomer and its 5,6-dihydro- and 5,6,13,14-tetrahydro derivative

PGF has ₁ , its 15epi-isomer and its 13,14-dihydro derivative.

Example 2 ; lSS-Hydroxy-g-keto-Scis.! Pci s.13 trans-prostatrienoic acid lysylamide

a) 159 mg of prostaglandin A are stirred with 167 mg of 2,2-dithiodipyridine and 199 mg of triphenylphosphine in 5 ml of xylene at 20 ° C. for 24 hours. After evaporation of the solvent, the remaining oil is chromatographed on 100 g of Sephadex LH 20 with methylene chloride + 2% methanol, the 2-thiopyridyl ester of prostaglandin A _{2 being} obtained.

b) 131 mg of prostaglandin A ₃ -2-thiopyridyl ester are stirred with 93 mg of lysergylamine in 5 ml of tetrahydrofuran at 20 ° C. for 24 hours. The reaction mixture is chromatographed on 100 g Sephadex LH 20 using methylene chloride + 0.5% methanol to give the title compound _t
IR: 3450, 1730, 1710 cm " ¹

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Analogously to Example 2, roan is added

a) 15S-Hydroxy-9-keto-10cis, 13trans-prostadiensMuredihydrolysergylamid,
(IR: 3450, 1705, 1665, 1520 cm " ¹ )

b) 15R-Hydroxy-9-keto-16R-methyl-2,3-trans - (-) - methylene-5,10cis-prostadienoic acid lysgylamide, (IR: 3450, 1700, 1665, 1520 cm " ¹ )

as well as to compounds of Examples 1 and I ca) to eg).

Example 3: lSS-Hydroxy-g-keto-Scis , lOcis, 13trans-prostate trienoic acid lysergy ester [method b)]

248 mg of 15S-hydroxy-lla-imidazol-l ^l -yl-9-keto-5cis, 13-transprostadienoic acid lysgyl ester are left to stand in 9 ml of methanol at room temperature for 30 hours and then the methanol is evaporated at room temperature. The methanol-free oily residue is immediately treated with methylene chloride +

0.25% methanol chromatographed on 100 g of Sephadex LH 20, giving the title compound ^ IR: 3450, 1730, 1710 cm " ¹

Analogously to Example 3 and using appropriate compounds of the formula IHa, in which A is imidazolyl, one arrives at

trienoic acid lysgyl ester (IR: 3560, 3350, 1720, 1695, 1600 cm " ¹ ) and to the 1SS-Hydroxy-y-keto-Scis ^ OciSilStrans-prostatrienic acid dihydrolyser (IR: 3555, 3350, 1730, 1705 cm" ¹ ) _y and the examples 2, 2a) and 2b).

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Example 4; ISS-Hydroxy-g-keto-purin-T'-yl-ScTsylStrans · - ■ prostadienoic acid and 15s-hydroxy-9-keto-11α-

[Method c)]

356 mg of pure prostaglandin A ₂ and 127 mg of purine are dissolved in 4 ml of absolute dimethylformamide and left to stand for 6 weeks at room temperature, the course of the reaction being checked by means of thin-layer chromatography on silica gel sheets (flow agent CHCl.j / 20% CH ₃ OH + 1%

Glacial acetic acid), After the reaction is complete, the dimethylformamide is evaporated at room temperature in a high vacuum and the oil obtained is chromatographed on 80 g of Sephadex LH 20 with methylene chloride + 1% methanol, resulting in a separation into a mixture of Ila-purin-7'-yl- and Ila Purin-9'-yl derivatives [mixture a)] and a mixture of the llo-purin-9'-yl derivative and prostaglandin A ₂ f mixture b)] is achieved.

The mixture a) is chromatographed twice on Sephadex, whereupon 15S-hydroxy-9-keto-lla-purin-7'-yl-5cis _/ 13transprostadienoic acid is obtained as that with a stronger polarity.

IR: 1745, 1705, 1600, 1560 cm " ¹

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- * 7-100- ^ 544

Isolation of 15S-hydroxy-9-keto-lla-purin-9 * -yl-5eis _f 13trans-prostadienoic acid

148 mg of the mixture b) defined above are mixed with 23 mg of imidazole and left to stand at room temperature for 1 1/2 hours. The reaction product is then dissolved in 100 ml of methylene chloride and shaken with 20 ml of approx. 0.01 N hydrochloric acid. The organic phase is separated off, dried, filtered and evaporated to give the pure title compound.

IR: 1745, 1705, 1600, 1580, 1500 cm " ¹

Example · 5 ; TSS-Hydroxy-lla-imidazol-l'-yl-g-keto-Scis, • IStrans-prostadienoic acid [method c) 3

315 mg of prostaglandin A ₂ and 96 mg of imidazole are combined in 3 ml of methylene chloride, so that a clear solution is formed. After evaporation of the solvent at room temperature, the remaining oil is left to stand for three days at room temperature and the reaction product is chromatographed on 100 g of Sephadex LK 20 with methylene chloride + 1% methanol, the title compound being obtained.

IR: 3350, 3300, 1740, 1710, 1695 (shoulder), 1600 cm " ¹ UV: 208 nm (= 6500), 276 nm (= 800)

709846/0675

IGO-4544

Analogous to example 5 one arrives at

a) lSS-hydroxy-lloc-imidazol-l'-yl-S-keto-lStrans-prostenic acid,
IR: 3450, 1740, 1710, 1695 (shoulder) cm " ¹

b) lSS-Hydroxy ^ -keto-lla-l ¹ , 2 ¹ , 4 ¹ ^ rIaZoI-I'-yl-5cis, 13trans-prostadienoic acid,
IR: 1745, 1705, 1505 cm " ¹

c) LSS-Hydroxy ^ -keto-llcc-pyrazol-l'-yl-5cis, 13transprostadienoic acid,

ir 1745, 1705, 1505 (small) cm " ¹

d) ISR-hydroxy-g-keto-lla- (6'-dimethylamine) -purine-9-yl-5cis, 13-trans-prostadic acid

IR: 1745, 1705, 1600, 1560 cm " ¹

e) lSR-hydroxy-lla-imidazol-l'-yl-g-keto-SciSjlStransprostadienäure, IR 1740, 1700, 1500 cm ",

f) 16,16-Dimethyl-15 R-hydroxy-lla-imidazol-1'-yl-9-keto-2,3-trans - (-) - methylene-5cis, 13trans-prostadic acid IR: 1740, 1700 cm " ¹ .

g) 15S-hydroxy-9-keto-IIIa- (6 ^I -dimethylamino) -purin-9'-yl-SciSjlStrans-prostadienoic acid,

IR: 1745, 1705, 1600, 1565 cm " ¹

h) llR-hydroxy-lla-imidazol-l'-yl-g-keto-ieR-methyl-SciST prostenic acid,
IR: 1745, 1705, 1500 cm " ¹

7098A6 / 0675

lOG- ^ 544

i) ISS-Acetoxy-llcc-imidazol-l'-yl-9-keto-Scis, 13transprostadienoic acid,
IR: 1745, 1735 (shoulder), 1700 cm " ¹

j) 15-Cyclohexy1-lla-imidazol-l'-yl-lSR-hydroxy ^ -keto-16,17,18,19,20-pentanor-5cis, 13trans-prostadienoic acid, IR: 1740, 1700 cm " ¹

k) 15R-Hydroxy-lla-imidazol-l ^l -yl-9-keto-16R-methyl-2,3-trans (-O-nethylene-scis-prostadic acid, IR: 1740, 1700 cm " ¹

" Example 6; 'l-SS-Hydroxy-lla-iWidazol-l'-yl- ^ g- and 9ß-n-

• octanoyl-5cis , 13trans-prostadienoic acid

a) 150 mg of prostaglandin A ₂ are mixed with one equivalent of dihydropyran and a catalytic amount of p-toluenesulfonic acid in 10 ml of methylene chloride at 0 ° C. and worked up in a manner known _{per se, the prostaglandin A 2} -15-tetrahydropyran-2'- ylether receives.

b) Using the method described in Example 5, the ether obtained under a) is converted into the lla-imidazol-l'-yl-9-keto-15S-tetrahydropyran-2 * -yloxy-5cis, 13trans-prostadic acid transferred.

c) 180 mg of the compound obtained under b) are dissolved in 10 ml of dioxane with 35 mg of sodium borohydride at room temperature reduced and worked up, with 9 <x-hydroxy and 9β-hydroxy-lla-imidazol-l'-yl-15S-tetrahydropyran-2'-yloxy-5cis, 13trans-prostadienoic acid receives.

709846/0675

- ICO- 4544

IB

d) 300 mg of the mixture of 9α- and 9β-hydroxy derivatives obtained under c) in 10 ml of acetone and 3 ml of pyridine are at -10 ° C with 0.4 ml of n-octanoyl chloride in 10 ml Acetone added. The reaction mixture is left to stand at room temperature for 16 hours, then with Dilute methylene chloride, wash with aqueous phosphate buffer (pH 7.5) and concentrate to give a mixture the 9a- and 9β-n-octanoyloxyderivate obtained.

e) the cleavage of the tetrahydropyranyl group of the 9a- and 9β-n-octanoyloxy derivatives [obtained under d)] takes place using 4.5 ml of a mixture of acetic acid / water / acetone (1: 1: 1) and heating to 60 ° C for 30 minutes. The reaction mixture is prepared in a conventional manner using chromatography Sephadex LH 20 (eluent methylene chloride + 1% methanol) worked up, using the pure α- and ß-title compounds receives separately.

70984 67 0675

Claims (7)

Claims; Process for the production of ergolin-8-yl-alkyl esters, thioesters and amides of prostanoic acids, characterized in that a corresponding prostanoic acid or its reactive acid derivative with 8-hydroxyalkylergoline, 8-thioalkylergoline or 8-aminoalkylergoline implements. 2. The method according to claim 1 for the preparation of compounds of formula I, D * ^ Y Z-COTR * X R, ^0R 3 wherein, in the prostanoic acid moiety, D is a group of the formula Dl D2 709846/0675 ORIGINAL INSPECTED /
OH OH D4 D5 or D7 stands where A 100-4544 D6 a residue of the formula a)
α β a) wherein 1 to 3 of the methine groups denoted by α, β, Γ or B have been replaced by nitrogen or a radical of the formula b) b) 709846/0675 100-4544 means in which either one of the ring members L and M is nitrogen and the other is methine, or L and H are each nitrogen, 1 to 3 of the methine groups denoted by <* i ß / T or S can be replaced by nitrogen, and the six-membered ring unsubstituted or mcnosubstituted by alkylamino, dialkylamino, alkoxy, alkylthio or halogen, the alkyl groups independently of one another have 1-5 carbon atoms, X for -CH ₂ -CH ₂ - or -CH = CH- (trans), Y for -CH ₂ -CH ₂ - or -CH = CH- (cis or trans), CH Z for -CH ₂ -CH ₂ - or -CH-> CH- (cis or trans) R _{1 is} an alkyl group with 1-10 carbon atoms or a cycloalkyl group with 3-9 carbon atoms, R _{2 is} hydrogen or an alkyl group with 1-7 carbon atoms, R ₃ and R. are independently hydrogen, an alkanoyl group with 1-20 carbon atoms or the Benzoyl group, w oxygen, sulfur or the -NH group, and the alkylergoline part R for the remainder of the formula II II 709846/0675 100-4544 where η is 1 or 2, R _{§ is} hydrogen, an alkyl group with 1-4 carbon atoms or the benzyl group, R- and R ₁ . independently represent hydrogen or halogen, R_ is an alkyl group with 1-4 carbon atoms, but not tert. Butyl means 1) R "and Rg each for hydrogen, or 2) R _ß and Rq together form a bond, or 3) R _ß for hydrogen and R for an alkoxy group with 1-4 carbon atoms, characterized in that one a) for the preparation of compounds of the formula I, compounds of the formula III, Z-COOH _TTT III ¹ X " wherein D, R., R ₂ , R_, X, Y and Z have the above meaning, or their reactive acid derivatives with compounds of the formula IV, H-WR IV . wherein R and W have the above meaning, converts, or k) _{for the} preparation of compounds of the formula Ia, 709846/0675 iÜÜ-4b44 Z-COfR Yes wherein R / R., R ₂ / R-, W, X, Y and Z have the above meaning / by converting compounds of the formula Ib ₁ Z-COiR Ib in which A, R, R, R ₂ , R ₃ , W, X / Y and Z have the above meanings, the radical A splits off. 3. Process for the preparation of compounds of the formula III in which D is D6 or D8, characterized in that one c) for the preparation of compounds of the formula IHa where A, sit, -COOH IHa R ₂ , R ₃ , X, Y and Z have the above meaning 7098A6 / 0675 Compounds of the formula HIb, 6 - iCO-4544 IHb in which R., R_, R, X, Y and Z have the above meaning, reacts with the amines introducing the radical A .. 4. The method according to claim 2 for the production of compounds of formula I, wherein (a) D is D3, in which the side chain in position 11 is not Ila-OH, D7 or D8; (b) W means sulfur? (c) R is dihydrolysergyloxy;
(d) η is 2; (e) R _{5 represents} an alkyl group having 1-4 carbon atoms or the benzyl group; (f) at least one of the substituents R ₄ . and R, _{Λ is} halogen; (g) R _{7 represents} an alkyl group having 2 or more carbon atoms; (h) Rg is hydrogen and R _g is an alkoxy group having 1-4 carbon atoms; 709846/0 67 5 7 - 100-454 " (i) the 8-ergoline side chain is in the α configuration} (j) R. an alkyl group and / or
(k) R- mean an alkanoy group. 5. The method according to claim 2 for the preparation of compounds of formula I, wherein R stands for Dihydrolysergylamino}
CH- Z stands for -CH -CH-} D for Dl, D2, D5, D6 and / or
Y stands for -CH ₂ -CH ₂ -. 6. The method according to claim 2 for the preparation of compounds of the formula I, wherein Z is -CH.-CH--. 7. The method according to claim 3 for the preparation of compounds of the formula IHa, wherein Z stands for -CH> CH-} D stands for Dl, D2, D5 _# D6} Y stands for -CH ₂ -CH ₂ -} 709846/0675 "■" ■■%; ■ ¹⁰ 27OT91 5 X stands for -CH = CH-} R. stands for alkyl and / or R _{1 stands} for alkanoyl. 3700 / IG / SE 709846/0675